Alarmins and immunity

Abstract

More than a decade has passed since the conceptualization of the "alarmin" hypothesis. The alarmin family has been expanding in terms of both number and the concept. It has recently become clear that alarmins play important roles as initiators and participants in a diverse range of physiological and pathophysiological processes such as host defense, regulation of gene expression, cellular homeostasis, wound healing, inflammation, allergy, autoimmunity, and oncogenesis. Here, we provide a general view on the participation of alarmins in the induction of innate and adaptive immune responses, as well as their contribution to tumor immunity.

Keywords: alarmin; damage-associated molecular pattern; dendritic cells; immune response; tumor immunity.

Figure 1

Signaling pathways triggered by alarmins. Alarmins produced in response to danger (injury or infection) engage primarily pattern-recognition receptors (PRRs) and Gαi protein-coupled receptors (GiPCRs) for inducing leukocyte activation and recruitment, respectively. Most alarmins triggers Toll-like recetpors, IL-1R1, ST2, or receptor for advanced glycation endproducts (RAGE) for the activation of various transcription factors (TFs) such as NF-κB, IFN-responsive factors (IRFs) that, after nuclear relocation, coordinately promote the transcription of proinflammatory chemokines and cytokines including pro-IL-1β and pro-IL-18. Some alarmins (e.g. uric acid) internalized as phagocytic vacuoles disrupt lysosome upon fusion, leading to the release of proteases (e.g. cathepsin B) to promote the oligomerization and assembly of NLRP3 inflammasome. Several alarmins (e.g. ATP, cathelicidin, defensins) activate the purinergic receptor P2X7 to induce K⁺ efflux, which also promotes the oligomerization and assembly of NLRP3 inflammasome. Oligomerization and assembly of NLRP3 inflammasome trigger the cleavage of pro-caspase 1 into active caspase 1 (CASP1) that are responsible for the maturation of IL-1β and IL-18. Most alarmins also interact with GiPCRs (e.g. CCR6, CCR2, P2Ys, etc) to activate phospholipases (PLCβ or PLCγ). PLCβ or PLCγ induce the activation of PI3K, the small GTPases (Rac and Rho), Akt, Erks, LIMK, and PKC, which coordinately promote cell migration.